ID #1006 Targeting the CDK8:Transcription-coupled DNA repair axis to overcome radioresistance in MYC-driven medulloblastoma

Group 3 Medulloblastoma (MB) is defined by MYC-driven transcriptional addiction, a state where global RNA Polymerase II (Pol II) amplification fuels rapid growth but creates a lethal vulnerability to transcriptional stress. While radiotherapy (RT) remains a standard of care for these patients, the mechanisms by which MYC-hyperactive cells resolve conflicts between high-velocity transcription and RT-induced DNA lesions remain a critical gap in our clinical understanding. Recent work established CDK8 as a key coordinator of transcriptional regulation and ribosome biogenesis and a therapeutic vulnerability in MYC-driven medulloblastoma. Building on this, we demonstrate that CDK8 additionally serves as a master regulator of transcriptional resilience and contributes to radiation response in tumors. Analysis of patient tissue and patient-derived xenografts (PDX) reveals that CDK8 is significantly elevated in tumors that relapse following RT, suggesting it as a primary driver of acquired radioresistance. Mechanistically, CDK8 coordinates the cellular response to genotoxic stress by maintaining the Transcription-Coupled Nucleotide Excision Repair (TC-NER) program. Transcriptomic profiling and GSEA demonstrate that CDK8 is essential for the expression of the TC-NER machinery, which is required to clear DNA lesions within actively transcribed genes. Loss of CDK8 leads to a profound failure in the recovery of RNA synthesis following genotoxic insult. Mechanistically, CDK8 antagonism leads to stalling of p-Ser2 Pol II at RT-induced DNA lesions, creating a “transcriptional traffic jam” that prevents the execution of the canonical p53-p21 repair program. This failure triggers a catastrophic signaling switch; while p21 induction is lost, persistent damage signals drive hyper-activation of the ATM-CHK2 axis, locking cells into a permanent G2/M arrest. By uncoupling MYC-driven transcription from its repair support, CDK8 inhibition converts an oncogenic strength into a lethal liability. This strategy achieves potent radiosensitization, clearing stalled Pol II complexes and inducing durable, long-term remissions in orthotopic MYC-amplified PDX models. Our findings position the CDK8:TC-NER axis as a high-priority therapeutic target to overcome treatment resistance in the most aggressive subtypes of medulloblastoma.